A Whole Virus Pandemic Influenza H1N1 Vaccine Is Highly Immunogenic and Protective in Active Immunization and Passive Protection Mouse Models

Kistner, Otfried; Crowe, Brian A.; Wodal, Walter; Kerschbaum, Astrid; Savidis-Dacho, Helga; Sabarth, Nicolas; Falkner, Falko G.; Mayerhofer, Ines; Mundt, Wolfgang; Reiter, Manfred; Grillberger, Leopold; Tauer, Christa; Graninger, Michael; Sachslehner, Alois; Schwendinger, Michael G.; Brühl, P; Kreil, Thomas R.; Ehrlich, Hartmut J.; Barrett, Perry

doi:10.1371/journal.pone.0009349

Cited by 43 publications

(36 citation statements)

References 25 publications

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“…According to Kistner et al [25], the higher immunogenicity of whole-virion vaccines compared to split vaccines is due to their ability to induce both Th1 and Th2 immune responses. Moreover, the immunity conferred by inactivated whole-virion vaccines shows cross-protection, i.e.…”

Section: Discussionmentioning

confidence: 99%

Preliminary Assessment of Safety and Immunogenicity of an Inactivated Whole-Virion Vaccine against Influenza А (H1N1) Pdm09 Containing Aluminum Hydroxide Adjuvant: A Randomized, Blinded Phase I Clinical Study

Tabynov¹,

Khairullin²,

Kydyrbayev³

et al. 2013

J Vaccines Vaccin

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We performed a randomized, blinded, dose-dependent placebo-controlled phase I clinical study of single administration of Refluvac®, a monovalent inactivated whole-virion vaccine against pandemic influenza А (Н1N1) pdm09 containing aluminum adjuvant, in healthy volunteers aged 18-60. Single intramuscular injection at doses of 3.75, 7.5, or 15.0 µg hemagglutinin (НА) identified no safety issues in adult volunteers (n=12 per group); no severe or serious vaccination-related adverse events were observed. Only mild/moderate local adverse events (n= 3/12, 25% in 7.5 µg НА arm,) and one moderate systemic reaction (n=1/12, 8.3% in 15.0 µg НА arm) were observed. In volunteers vaccinated at 3.75 µg HA, the proportion of subjects with 4-fold seroconversion was 75%, the level of seroprotection was also 75%, the antibody titer increase was 10.7-fold, and the geometric mean titer (GMT) of antibodies to А/H1N1p-dm09 was 53.4; for the 7.5 µg HA dose, the proportion of 4-fold seroconversion was 75%, the antibody titer increase was 32.0-fold, the GMT was 160.0, and the level of seroprotection was 75%. When administered at a higher dose (15 µg HA), the proportion of subjects with protective antibody titers increased from 75% to 83%; however, the GMT and antibody titer increase were not significantly different (P>0.05) to the group vaccinated at 7.5 µg HA. Phase II clinical studies of the 3.75 and 7.5 µg HA doses of Refluvac® vaccine should be performed in a larger cohort of healthy volunteers aged 18-60. The effective immunogenicity of low doses of Refluvac® vaccine may enable increased production of pandemic influenza vaccines, and thus provide more people with a safe, effective vaccine. Citation: Tabynov K, Khairullin B, Kydyrbayev Z, Sandybayev N, Stukova M, et al. (2013) [16]. Notably, the lowest НА content required to induce a sufficient immune response was seen when whole-virion or adjuvant-containing vaccines were used. The НА content is the most important limiting factor when developing a pandemic vaccine, as existing production capacities for seasonal influenza vaccines are rather limited and are unable to meet the worldwide demand for a pandemic vaccine. Thus, a higher number of doses of vaccines with low antigenic loads can be manufactured. Journal of Vaccines & VaccinationOn this basis, in order to create a pandemic vaccine to protect the population of Kazakhstan and neighbouring Central Asian countries, an inactivated whole-virion vaccine (Refluvac®) against Н1N1pdm09 containing aluminum hydroxide adjuvant was developed at the Research Institute for Biological Safety Problems (Kazakhstan). We previously demonstrated the safety and immunogenicity of this vaccine in preclinical studies conducted at research centers in Russia (The Research Institute of Influenza, Institute of Toxicology, Chemical and Pharmaceutical Academy) and Kazakhstan (The National Center for Expertise on Drugs) [17,18]. On the basis of these preclinical studies, Refluvac® vaccine was recommended for a phase I clinical study of single intra...

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Section: Discussionmentioning

confidence: 99%

Preliminary Assessment of Safety and Immunogenicity of an Inactivated Whole-Virion Vaccine against Influenza А (H1N1) Pdm09 Containing Aluminum Hydroxide Adjuvant: A Randomized, Blinded Phase I Clinical Study

Tabynov¹,

Khairullin²,

Kydyrbayev³

et al. 2013

J Vaccines Vaccin

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“…Recently, there is a great concern that the reassortants between avian H5N1 and influenza A (H1N1) could cause a pandemic of new influenza virus in humans [33]. Compared with HPAI H5N1, H1N1 virus has higher morbidity and lower mortality.…”

Section: Discussionmentioning

confidence: 99%

Cross clade prophylactic and therapeutic efficacy of polyvalent equine immunoglobulin F(ab′)2 against highly pathogenic avian influenza H5N1 in mice

Zhao

Fang

Chen

et al. 2011

International Immunopharmacology

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“…The nonadjuvanted inactivated whole-virus Vero cell culturederived H9N2 vaccine was manufactured using a reverse genetics (RG)-modified strain A/chicken/Hong Kong/G9/97 (H9N2) virus (NIBRG-91) obtained from the National Institute for Biological Standards and Control (NIBSC) (United Kingdom). This vaccine was produced using a procedure identical to that used for the manufacture of licensed H5N1 and 2009 pandemic H1N1 (H1N1pdm09) whole-virus vaccines (30,31). Briefly, the vaccine virus strain was grown in Vero cell culture and, after harvest, was double inactivated with formalin and UV irradiation and purified by continuous sucrose gradient centrifugation and ultra-/diafiltration steps prior to formulation.…”

Section: Methodsmentioning

confidence: 99%

Phase I/II Randomized Double-Blind Study of the Safety and Immunogenicity of a Nonadjuvanted Vero Cell Culture-Derived Whole-Virus H9N2 Influenza Vaccine in Healthy Adults

Aichinger

Grohmann-Izay

Velden

et al. 2014

Clin. Vaccine Immunol.

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dStudies on candidate pandemic vaccines against avian influenza viruses have focused on H5N1, but viruses of other subtypes, such as A/H9N2, are also considered to have pandemic potential. We investigated the safety and immunogenicity of two immunizations with one of five different antigen doses (ranging from 3.75 to 45 g of hemagglutinin antigen) of a nonadjuvanted whole-virus G9 lineage H9N2 influenza virus vaccine in healthy adults aged 18 to 49 years. The antibody responses were measured by hemagglutination inhibition (HI), microneutralization (MN), and single radial hemolysis (SRH) assays. To investigate a hypothesis that previous exposure to H2N2 viruses in subjects born in or before 1968 might prime for more robust antibody responses to H9N2 vaccination than that in subjects born after 1968, a post hoc age-stratified analysis of antibody responses was done. Both vaccinations in all dose groups were safe and well tolerated. No vaccine-related serious adverse events were reported, and the majority of the adverse reactions were rated as mild. The rates of injection site reactions were lower in the 3.75-g-and 7.5-g-dose groups than those in the higher-dose groups; the rates of systemic reactions were similar across all dose groups. The seroprotection rates among the different dose groups 21 days after the second immunization ranged from 52.8% to 88.9% as measured by HI assay, from 88.7% to 98.1% or 82.7% to 96.2% as measured by MN assay (MN titer cutoffs, 1:40 and 1:80, respectively), and from 94.2% to 100% as measured by SRH assay. Higher antibody responses were not induced in subjects born in or before 1968. These data indicate that a nonadjuvanted whole-virus H9N2 vaccine is well tolerated and immunogenic in healthy adults. (This study has been registered at ClinicalTrials.gov under registration no. NCT01320696.) A number of avian influenza virus subtypes have caused zoonotic infections in humans, including those of subtypes H5N1 (1), H9N2 (2), and, most recently, H7N9 (3) and H10N8 (4). Because the human population is largely immunologically naive to such viruses, there are concerns that a pandemic situation might occur if any of these viruses gains the capacity for efficient human-to-human transmission. The development of candidate pandemic vaccines to counter the threat of a pandemic resulting from avian influenza viruses is thus an important part of global pandemic preparedness programs (5, 6). To date, this effort has been concentrated largely on the development of candidate pandemic vaccines based on influenza viruses of the H5N1 subtype. A number of clinical studies have demonstrated whole-virus inactivated H5N1 vaccines to be immunogenic in adult, elderly, and pediatric populations without a requirement for adjuvantation (7-11). In the present study, we extend the clinical investigation of nonadjuvanted whole-virus avian influenza vaccines to include a vaccine against the H9N2 influenza virus subtype, which is enzootic in poultry across the Middle East and Asia and is considered to have pandemic po...

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A Whole Virus Pandemic Influenza H1N1 Vaccine Is Highly Immunogenic and Protective in Active Immunization and Passive Protection Mouse Models

Cited by 43 publications

References 25 publications

Preliminary Assessment of Safety and Immunogenicity of an Inactivated Whole-Virion Vaccine against Influenza А (H1N1) Pdm09 Containing Aluminum Hydroxide Adjuvant: A Randomized, Blinded Phase I Clinical Study

Preliminary Assessment of Safety and Immunogenicity of an Inactivated Whole-Virion Vaccine against Influenza А (H1N1) Pdm09 Containing Aluminum Hydroxide Adjuvant: A Randomized, Blinded Phase I Clinical Study

Cross clade prophylactic and therapeutic efficacy of polyvalent equine immunoglobulin F(ab′)2 against highly pathogenic avian influenza H5N1 in mice

Phase I/II Randomized Double-Blind Study of the Safety and Immunogenicity of a Nonadjuvanted Vero Cell Culture-Derived Whole-Virus H9N2 Influenza Vaccine in Healthy Adults

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